Cognitive Impairments in Drug-Naive Patients With First-Episode Negative Symptom–Dominant Psychosis

Key Points Question Does a distinct subtype of first-episode psychosis (FEP) characterized by predominant negative symptoms (negative symptom–dominant [NSD] psychosis) exhibit specific cognitive impairments? Findings In this cross-sectional study, 788 patients with NSD exhibited more pronounced cognitive impairment compared with those with positive symptom–dominant or general symptom–dominant psychosis, particularly in processing speed and attention domains. The severity of cognitive impairment was positively associated with the intensity of negative symptoms, underscoring the pivotal role of negative symptoms in shaping cognitive deficits among individuals with first-episode psychosis. Meaning The findings of this study suggest the existence of a distinct clinical subtype, NSD, within FEP, characterized by pronounced cognitive impairment.


Introduction
Psychosis is a severe mental disorder characterized by detachment from reality and encompassing symptoms such as hallucinations, delusions, and disorganized thinking.Cognitive impairments are commonly observed throughout the developmental trajectory of psychosis, 1 from the prodromal phase [2][3][4] to the first episode and the terminal stages of the illness.Patients with psychosis manifest deficits in attention, memory, executive function, and social cognition. 5,6These cognitive deficits substantially impact daily activities and quality of life. 7In addition to cognitive impairment, psychosis is associated with positive (eg, hallucinations and delusions) and general (eg, depressive and anxious mood) symptoms.However, negative symptoms, such as diminished emotional expression, social withdrawal, decreased motivation, and reduced speech, are core features of psychosis, involving a reduction in or absence of normal behaviors, emotions, and motivations, and appear to be associated with cognitive functioning. 8Studies have consistently reported a robust association between negative symptoms and cognitive impairment, [9][10][11] specifically in attention, memory, and executive functioning. 6 contrast, although cognitive deficits may occur in individuals with positive or general symptoms, the association between cognitive functioning and these symptoms is less evident than that between cognitive functioning and negative symptoms. 12This highlights the unique cognitive characteristics associated with negative symptoms of psychosis.Understanding the intricate association between cognitive function and the negative symptoms of psychosis is paramount, as it can provide insights into the underlying mechanisms and support the development of targeted interventions. 13By addressing cognitive impairments that contribute to negative symptoms, clinicians can potentially improve overall outcomes and enhance the quality of life of patients with psychosis.Consequently, further research in this area is essential to advance our knowledge and refine clinical interventions for individuals with negative symptoms of psychosis. 14 this study, our aim was to conduct a comprehensive analysis of the associations between cognitive functioning and psychosis subtypes, including negative symptom-dominant (NSD), positive symptom-dominant (PSD), and general symptom-dominant (GSD) first-episode psychosis (FEP), while also addressing the methodologic limitations of previous research in this field.Previous studies [15][16][17] had small sample sizes, confounding issues of concomitant antipsychotic use, and participants with late-stage illness.By evaluating a larger sample size and carefully controlling for potential confounding factors, our study sought to provide a more robust understanding of the specific cognitive characteristics associated with NSD psychosis.

Study Design and Participants
The cross-sectional study was led by the Shanghai Mental Health Centre (SMHC), and all procedures involving the participants were approved by the research ethics committee of SMHC.The research ethics committees at the different sites approved the study.Written informed consent was obtained from all participants during recruitment.For participants younger than 18 years, informed consent was provided by both the participants and their parents.No financial compensation was provided.All procedures conducted in this study complied with the ethical standards of the relevant national and institutional committees on human experimentation and the 1975 Declaration of Helsinki, revised in Symptoms Scale (PANSS) 18 and Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) [19][20][21] assessments were included in the data analysis.None of the participants in this study had previously received psychotropic medications.Furthermore, none met the exclusion criterion of a history of substance abuse or dependence.The sample size for this study was determined based on available resources meeting specified criteria within the investigation's timeframe, rather than through formal statistical calculations.While the sample size was not predetermined, it aligns with the study's criteria and objectives, reflecting the available population within the specified timeframe.Among the 788 individuals with FEP, there were 719 (91.2%) cases of schizophrenia, 33 (4.2%) cases of acute and transient psychotic disorder, 20 (2.5%) cases of persistent delusional disorder, and 16 (2.0%)cases of schizoaffective disorder.

Clinical Symptom Assessments
Clinical psychopathologic status was assessed using the PANSS, 18 which consists of 30 items divided into 3 psychopathology subscales: positive (PANSS-P; items P1-P7), negative (PANSS-N; N1-N7), and general (PANSS-G; G1-G16).Each item (symptom) was rated on a 7-point Likert scale (1 = absent and 7 = extreme).Structured clinical interviews were conducted by 23 senior psychiatrists (T.Z., L.X., and Q.H.) who completed the training required for this type of investigation.The interrater reliability of the PANSS, as per the ratings of the trained interviewers, ranged from 0.76 to 0.92.

Group Criteria
To make the 3 PANSS subscales comparable, we conducted a full sample-based Z score transformation.The NSD psychosis group was defined according to the Z scores of PANSS-N, which were higher than those of PANSS-P and PANSS-G.Similarly, the PSD psychosis group was defined according to the Z scores of PANSS-P, which were higher than those of PANSS-N and PANSS-G.The GSD psychosis group was defined according to the Z scores of PANSS-G, which were higher than those of PANSS-P and PANSS-N.

Neurocognitive Function Assessments
Neurocognitive performance was assessed using the Chinese version of the MCCB. 19The MCCB assessment was performed following the standardized guidelines of the test manual, and consistent with the original MCCB, the following 8 subtests were included in the present study: (1)

Statistical Analysis
Data analysis was conducted in 2023.The patients were divided into NSD, PSD, and GSD groups, and neurocognitive performance was compared.Quantitative variables are expressed as means (SDs) and qualitative variables as frequencies (percents).Analysis of variance was used to examine quantitative variables and the χ 2 test was used to examine qualitative variables, with a 2-tailed, paired significance threshold of P < .05.For pairwise comparisons, post hoc least significant difference correction was applied to adjust for multiple testing.Effect sizes were calculated using Cohen d for mean comparisons.The mean scores of the neurocognitive tests in the 3 groups were converted to Z scores on the basis of the mean (SD) of the overall sample.The association between clinical symptoms and neurocognitive performance was explored via the Pearson correlation coefficient test, and the P value was corrected (P < .05/ 24 was considered significant) by controlling the familywise error at the 0.0021 level using Bonferroni correction.Given that there were 3 groups (NSD, PSD, and GSD) and 8 MCCB tests, a total of 24 correlation analyses were conducted.In addition, logistic regression was performed to examine the discriminatory power of individual neurocognitive variables in identifying patients with NSD while controlling for age and sex.In the logistic analysis, the NSD group was coded as 1 and the PSD and GSD groups were coded as 0.
Statistical analysis was performed with SPSS Statistics for Windows, version 20.0 (IBM Corp).

Demographic and Clinical Characteristics
In total, 788 participants (men, 399 [50.6%]; women, 389 [49.4%]) with a median age of 22 (IQR, 17-28) years were included.The demographic and clinical characteristics of the 788 participants are reported in Table 1.There were no significant differences in mean age among the NSD, PSD, and GSD groups (F = 1.707;P = .18).The proportion of men and women was equivalent among the groups (χ 2 = 0.243; P = .89).
Specifically, having a higher level of negative symptoms was associated with lower neurocognitive performance.However, an association was not observed between neurocognitive tests and positive and general symptoms, except for a correlation between NAB mazes and positive symptoms (r = −0.147;P < .001)(Figure 3; eFigure in Supplement 1).

Discussion
In this study, we conducted a large-scale investigation of Chinese patients with FEP and obtained several key findings.To our knowledge, this is the largest study to compare patients with FEP who are drug-naive with NSD psychosis with those with PSD and GSD psychosis in China.We found that patients with NSD exhibited more pronounced cognitive impairment than did those with PSD and GSD.Specifically, the cognitive differences between the NSD and PSD groups as well as the NSD and GSD groups were most notable in the domains of processing speed (BACS symbol coding, Trail Making A, and Category Fluency) and attention (CPT-IP).Patients with PSD and GSD showed no significant cognitive differences.Cognitive impairment was positively associated with the severity of negative symptoms.Most cognitive function tests used in our study were able to differentiate patients with NSD from those with PSD and GSD, which implies that cognitive assessments may serve as valuable tools for identifying and distinguishing patients with NSD.
In our study, patients with predominantly negative symptoms exhibited cognitive impairment, particularly in the domains of processing speed and attention, which may be related to the neural mechanisms associated with these symptoms.The negative symptoms of psychosis are thought to arise from disruptions in genetic variants of the dopamine pathway 22 and hypodopaminergic activity in the mesocortical pathway and prefrontal cortex, 23 which are responsible for cognitive and emotional processing.The dysfunction of these pathways may lead to slower information processing and lower attention, resulting in deficits in cognitive performance.Moreover, negative symptoms concerning the prefrontal and anterior cingulate cortices are often associated with structural and functional abnormalities in certain brain regions. 24A recent meta-analysis 24 of structural and functional brain abnormalities in patients with schizophrenia and persistent negative symptoms suggested that structural brain abnormalities are consistently located in the prefrontal, temporal, limbic, and subcortical regions, and functional alterations are concentrated in the thalamocortical circuits and the default mode network.[27] Additionally, negative symptoms, such as reduced motivation and social withdrawal, may contribute to decreased cognitive engagement and practice in daily activities, leading to a decline in cognitive abilities over time.Lack of engagement in cognitive tasks and reduced environmental stimulation may further exacerbate processing speed and attention impairments in these patients. 28minant negative symptoms can also decrease the ability of patients to focus on tasks or sustain attention for extended periods.An emotional antisaccade task from Navalón et al 29 found hypersensitivity to threat in patients with PSD schizophrenia and desensitization to socioemotional information in patients with NSD.Lack of motivation may result in reduced cognitive effort and attentional resources allocated to tasks, leading to cognitive impairment.
The association between negative symptoms and cognitive impairment is likely bidirectional.
While negative symptoms may contribute to cognitive deficits, cognitive impairment can also influence the severity and manifestation of these symptoms. 30,31For example, reduced processing speed and attention may hinder social and occupational functioning, leading to increased social Corrected P values by controlling the familywise error at the .0021(P < .05/ 24 was significant) level, using a Bonferroni correction.Shading indicates 95% CIs.withdrawal and diminished motivation.Further research is needed to investigate the precise mechanisms underlying the associations between negative symptoms, processing speed, and attentional impairment.Longitudinal studies could help elucidate the temporal association between these variables and provide insights into whether cognitive impairment precedes or follows the onset of negative symptoms.
Our findings highlight the existence of a clinical subtype within the population of patients with psychosis that is characterized by a predominance of negative symptoms and cognitive impairment. 32,33This subtype represents a distinct subgroup with unique clinical features that warrant further investigation and consideration in clinical practice. 32Identification of this specific clinical subtype has important implications for understanding the heterogeneity of schizophrenia and tailoring treatment approaches. 34,35

Limitations
Our study had several limitations.First, the use of a cross-sectional design restricted our ability to understand temporal changes in negative symptoms and cognitive functions.Furthermore, the assessment of negative symptoms primarily relied on observer-rated measures, which may have introduced bias and variability.Observer-rated assessments can be influenced by individual perceptions and the subjectivity of the raters.Including more objective measures, such as digital biomarkers, 39 would enhance the validity and reliability of negative symptom assessment.
Considering that cognitive impairments observed in patients with negative symptoms may be influenced by their IQ, another limitation is the lack of IQ measurements in our study.Including IQ assessment would provide a better understanding of cognitive functioning and allow for a more comprehensive analysis of cognitive impairment concerning negative symptoms.Additionally, we did not consider the influence of the duration of untreated psychosis on our findings.Duration of untreated psychosis has been shown to be associated with various clinical outcomes, 40,41 including symptom severity and cognitive functioning.The inability to account for duration of untreated psychosis in our study limited our understanding of this important variable on the association between negative symptoms and cognitive impairment.

Conclusions
This cross-sectional study provides findings suggesting that patients with FEP with NSD exhibit more-pronounced cognitive impairments than do those with PSD and GSD, particularly in the domains of processing speed and attention.The observed cognitive deficits in processing speed and attention in patients with NSD suggest that they may experience difficulties in efficiently processing information and maintaining sustained attention, which has major implications for daily functioning,

JAMA Network Open | Psychiatry
Cognitive Impairment in First-Episode Negative Symptom-Dominant Psychosis social interactions, and overall quality of life.Our findings underscore the need for a personalized approach to assessing and managing cognitive deficits associated with negative symptoms, which can potentially improve functional outcomes and enhance the overall well-being of patients with FEP.
part A of the Trail Making test (Trail Making A), (2) symbol coding of the Brief Assessment of Cognition in Schizophrenia (BACS) (BACS symbol coding), (3) Category Fluency Test (Category Fluency), (4) Continuous Performance Test-Identical Pairs (CPT-IP), (5) spatial span of the Wechsler Memory Scale-III (WMS-3 spatial span), (6) Hopkins Verbal Learning Test-Revised (HVLT-R), (7) Brief Visuospatial Memory Test-Revised (BVMT-R), and (8) Neuropsychological Assessment Battery: Mazes (NAB mazes).The interrater reliability of the MCCB, as per the ratings of the 12 trained raters, ranged from 0.80 to 0.96.To mitigate potential biases, we implemented measures to enhance the reliability and validity of data collection.The research team underwent comprehensive training in PANSS application to ensure consistency and reduce interrater variability.Additionally, rigorous protocols were enforced during neurocognitive assessments using the Chinese version of the MCCB in the development and validation of which our research team actively contributed.

Figure 2
Figure 2 presents the ESs across the 8 neurocognitive tests for comparison between the NSD, PSD, and GSD groups.In the comparison between the NSD and PSD groups, BACS symbol coding (effect size = 0.26), Trail Making A (effect size = 0.24), and HVLT-R (effect size = 0.20)-the top 3 tests-had the maximum ES.In the comparison between the NSD and GSD groups, CPT-IP (effect size = 0.21), Trail Making A (effect size = 0.20), and BACS Category Fluency (effect size = 0.19)-the top 3 tests-had the maximum ES.The ESs for comparisons between the PSD and GSD groups were smaller than those between the NSD and PSD as well as the NSD and GSD groups.

Figure 1 .P
Figure 1.Comparisons of Neurocognitive Performance Among Patients With Negative Symptom Dominant (NSD), Positive Symptom Dominant (PSD), and General Symptom Dominant (GSD) First-Episode Psychosis

Figure 3 .
Figure 3. Correlations Between Clinical Symptoms and Neurocognitive Performances Using Trail Making A, Brief Assessment of Cognition in Schizophrenia (BACS) symbol coding, Hopkins Verbal Learning Test-Revised (HVLT-R), and Wechsler Memory Scale-III (WMS-3) Spatial Span Tests

Table 2 .
Logistic Regression for Individual Neurocognitive Function Discrimination NSD From PSD and GSD, Adjusted by Age and Sex a The constant OR does not have a 95% CI associated with it, as it represents the baseline value and is not subject to variation.
38aditional diagnostic criteria for schizophrenia primarily focus on positive symptoms, such as hallucinations and delusions.However, our study highlights the need to recognize and address prominent negative symptoms and cognitive impairment experienced by some patients.Interventions that combine pharmacologic approaches with psychosocial interventions,36such as cognitive remediation37and social skills training,38may be particularly beneficial for individuals with this subtype.These findings underscore the importance of considering premorbid neurodevelopmental disorders, such as autism spectrum disorder, in the assessment of individuals with FEP, particularly those presenting with predominantly negative symptoms.Cognitive deficits observed in patients with FEP with predominant negative symptoms may overlap with those seen in individuals with autism spectrum disorder, including difficulties in attention, executive function, and processing speed.Therefore, it is crucial for clinicians to conduct a comprehensive assessment, including a detailed developmental history, to differentiate between FEP and premorbid neurodevelopmental disorders.Additionally, interventions tailored to address specific cognitive deficits and social impairments associated with autism spectrum disorder may be warranted, particularly in individuals presenting with negative symptoms in the absence of hallucinations or delusions.